Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
  • A61P5/40—Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating the activity of mineralocorticosteroids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• the present application relates to novel substituted 4-aryl-l, 4-dihydro-l, 6-naphthyridines, processes for their preparation, their use for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for treatment and / or pro - phylaxis of diseases, in particular of cardiovascular diseases.
• Aldosterone plays a key role in the maintenance of fluid and electrolyte homeostasis by promoting natural retention and potassium secretion in the epithelium of the distal nephron, which contributes to keeping the extracellular volume constant and thus to regulating blood pressure.
• aldosterone exerts direct effects on the structure and function of the cardiac and vascular system, although the underlying mechanisms are not yet exhaustively clarified [R E Booth, J P Johnson, J D Stockand, Adv Physiol. Educ 26 (1), 8-20 (2002)].
• Aldosterone is a steroid hormone that is produced in the adrenal gland. Its production is indirectly regulated quite significantly depending on renal perfusion. Any decrease in renal blood flow in the kidney leads to a release of the enzyme renin into the bloodstream. This in turn activates the formation of angiotensin H, which on the one hand narrows the arterial blood vessels, but on the other hand also stimulates the formation of aldosterone in the adrenals.
• the kidney acts as a blood pressure and thus indirect volume sensor in the bloodstream and counteracts through the renin-angiotensm-aldosterone system critical volume losses, on the one hand, the blood pressure is increased (angiotensin U effect), on the other hand by increased reabsorption of sodium and Water in the kidney of the filling state of the vascular system is compensated again (aldosterone effect).
• This control system can be disturbed in many ways pathologically.
• a chronic hypoperfusion of the kidneys eg as a result of cardiac insufficiency and the congestion of blood in the venous system caused thereby
• a chronically inflated release of aldosterone leads to an expansion of the blood volume and hereby strengthens the heart failure by a volume oversupply to the heart.
• a congestion of blood in the lungs with shortness of breath and edema in the extremities as well as ascites and pleural effusions may result; Kidney circulation continues to drop.
• the excessive aldosterone effect leads to a reduction in the potassium concentration in the blood and in the extracellular fluid.
• hyperaldosteronism is a crucial component in the pathogenesis and prognosis of heart failure, which may initially be elicited by differential injury, such as a myocardial infarction, myocarditis, or hypertension.
• Hyperaldosteronism Much rarer than the forms of hyperaldosteronism listed above are those diseases in which the disorder is found either in the hormone-producing cells of the adrenal gland itself or their number or mass is increased by hyperplasia or proliferation.
• Adenoma or diffuse hyperplasia of the adrenal cortex is the most common cause of the also called Conn syndrome primary hyperaldosteronism, whose guiding symptoms are hypertension and hypokalemic alkalosis.
• drug therapy with aldosterone antagonists is in the foreground [H.A. kuhn and J. Schirmeister (ed.), Internal Medicine, 4th ed., Springer Verlag, Berlin, 1982].
• aldosterone antagonists Another condition typically associated with elevation of plasma aldosterone concentration is advanced cirrhosis of the liver.
• the cause of the increase in aldosterone is mainly due to the impaired breakdown of aldosterone due to liver dysfunction.
• Volume overload, edema and hypokalaemia are the typical consequences that can be successfully alleviated in clinical practice by aldosterone antagonists.
• the effects of aldosterone are mediated through the mineralocorticoid receptor located intracellularly in the target cells.
• potent, non-steroidal and mineralocorticoid-receptor-selective antagonists offers the opportunity to circumvent this side-effect profile and thereby achieve a clear therapeutic benefit.
• the object of the present invention is to provide novel compounds which can be used as selective mineralocorticoid receptor antagonists for the treatment of diseases, in particular of cardiovascular diseases.
• EP 0 133 530-A, EP 0 173 933-A, EP 0 189 898-A and EP 0 234 516-A disclose 4-aryl-substituted l, 4-dihydro-l, 6-naphthy ⁇ dme or The pharmacological profile of these compounds is inter alia described in G. Werner et al, Naunyn-Schmiedeberg's Arch Pharmacol 344 (3), 337-344 (1991). Furthermore, l, 4-dihydro-l, 6-naphthy ⁇ dm-De ⁇ vate in WO 02/10164 as Kahumkanal ⁇ ffher for the treatment of different, especially urological diseases claims.
• 4-fluorenonyl or 4-chromenonyl-1,4-dihydropyridine derivatives as mineralocorticoid receptor antagonists are described in WO 2005/087740 and WO 2007/009670.
• WO 2006/066011 4-aryl-3-cyano-1,4-dihydropy ⁇ din-5-carboxylic acid esters and amides are disclosed as partly dual modulators of steroid hormone receptors and the L-type calcium channel, and in WO 2005/097118 compounds with 4-aryl-l, 4-dihydro-py ⁇ din core structure are claimed as aldosterone receptor Antagomsten.
• R 5 is hydrogen or halogen
• R 6 is methyl or ethyl
• R 7 denotes hydrogen, fluorine, chlorine, cyano, nitro, trifluoromethyl or (C 1 -C 4 ) -alkyl
• R 8 is hydrogen or fluorine
• R 9 is halogen, (C 1 -C 4 ) -alkyl, trifluoromethyl, (QC 4 ) -alkoxy or trifluoromethoxy,
• R 10 is cyano or nitro
• R 12 is hydrogen, halogen or (C r C 4) -alkyl
• D is CH, CR is 9 or N
• n is the number 0, 1 or 2
• R 13 is (C r C 6 ) -alkyl which may be substituted by (C 3 -C 7 ) -cycloalkyl or mono- to trisubstituted by fluorine, or phenyl which is substituted by halogen, cyano, (C 1 -C 4 ) -alkyl , Trifluoromethyl, (C 1 -Q) -alkoxy or trifluoromethoxy, or (C 3 -C 7 ) -cycloalkyl,
• R 2 is (C, -C 4) alkyl, trifluoromethyl, cyclopropyl, cyclobutyl, (C, -C 4) -alkoxy or (C 1 -C 4) - alkylthio,
• R 3 is (C 1 -Ce) -alkyl 5 (Ci-C 6) alkoxy, trifluoromethoxy, (C r C6) alkylthio, ammo, mono (C r C6) alkylamino or a group of the formula - 0-SO 2 -R 14 is
• R 14 is (C 1 -C 6) -alkyl, trifluoromethyl, (C 3 -C 7 ) -cycloalkyl, phenyl or 5- or 6-membered heteroaryl having up to two heteroatoms from the series N, O and / or S. .
• phenyl and heteroaryl for their part may each be mono- or disubstituted by identical or comparable eliminated, with halogen, cyano, nitro, (C r C4) alkyl, trifluoromethyl, (Ci-C 4) -
• Alkoxy and / or trifluoromethoxy can be substituted
• R 4 is hydrogen, fluorine, (C 1 -C 4 ) -alkyl, trifluoromethyl, (C 1 -C 4 ) -alkoxy, trifluoromethoxy, (C 1 -C 4 ) -alkylthio, amino, or di- (C 1 -C 4 ) -alkylamino,
• Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts.
• the compounds according to the invention can exist in stereoisomeric forms (enantiomers, diastereomers).
• the invention therefore includes the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner.
• the present invention encompasses all tautomeric forms.
• Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are not suitable for pharmaceutical applications themselves, but can be used, for example, for the isolation or purification of the compounds according to the invention.
• Physiologically acceptable salts of the compounds of the invention include acid addition salts of maleic acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
• salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid acetic acid, trifluoroacetic acid, prop
• Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, as exemplified and preferably ethylamine, diethylamine, trimethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, Triethanolamine, dicyclohexylamine, dimethylaminoethanol, procam, dibenzylamine, N-methylmorphohn, arginm, lysine, ethylenediamine and N-methylpiperidin.
• customary bases such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived
• Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of the solvates in which the coordination takes place with water. As solvates, hydrates are preferred in the context of the present invention
• the present invention also includes prodrugs of the compounds of the invention.
• prodrugs includes compounds which may themselves be biologically active or inactive, but are converted during their residence time in the body into compounds according to the invention (for example metabolically or hydrolytically)
• VAlkVl in the context of the invention are a straight-chain or branched alkyl radical having 1 to 6, 1 to 4 or 1 to 3 carbon atoms, preferably a straight-chain or branched alkyl radical having 1 to 4, particularly preferably having 1 to 3 carbon atoms, by way of example and by way of preference: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-ethylpropyl, n-pentyl, iso-pentyl and n-hexyl
• -cycloalkyl and (C 2 -C 15) -cycloalkyl in the context of the invention represent a monocyclic, saturated cycloalkyl group having 3 to 7 or 3 to 6 carbon atoms. Preference is given to a cycloalkyl radical having 3 to 6 carbon atoms. Examples which may be mentioned by way of example include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl
• fC r Cfi alkoxy.
• (Ci-C / O-alkoxy and f C 1 -Cf) -Akoxy are in the context of the invention for a straight-chain or branched alkoxy radical having 1 to 6, 1 to 4 or 1 to 3 carbon atoms is preferably a straight-chain or branched alkoxy radical From 1 to 4, more preferably from 1 to 3, carbon atoms by way of example and preferably: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy and n-hexoxy.
• CC 1 -CJ-AIkVUhIO and (C 1 -Cd) -AlkVUhIO in the context of the invention represent a straight-chain or branched alkylthio radical having 1 to 6 or 1 to 4 carbon atoms.
• Methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, tert-butylthio, n-pentylthio and n-hexylthio are preferably mentioned in the context of the invention are an amino group having a straight-chain or branched alkyl substituent which has 1 to 6 or 1 to 4 carbon atoms.
• a straight-chain or branched monoalkyl armno radical having 1 to 4 carbon atoms is preferred.
• straight-chain or branched dialkylammo radicals having in each case 1 to 4 carbon atoms by way of example and preferably N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, N-tert-butyl-N-methylamino, N, Ethyl-Nn-pentylammo and Nn-hexyl-N-methylamino.
• 5 or 6-membered heteroaryl in the context of the invention is an aromatic heterocycle (heteroaromatic) having 5 or 6 Rmgatomen containing one or two ring heteroatoms from the series ⁇ , O and / or S and via em Rmg- Exemplary and preferred are furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyridyl, Py ⁇ midmyl, Py ⁇ dazinyl and pyrazmyl
• Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Preference is given to fluorine or chlorine.
• radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be mono- or polysubstituted. In the context of the present invention, the meaning is independent of one another for all radicals which occur repeatedly. Substitution with em, two or three identical or different substituents is preferred. Substitution with a substituent is very particularly preferred
• R 7 is hydrogen, fluorine, chlorine or cyano
• R * is fluorine, chlorine, methyl or ethyl
• R 11 is chlorine, bromine, (C r C4) alkyl, trifluoromethyl, (QC ⁇ alkoxy, trifluoromethoxy, or trifluoromethylthio,
• n is the number 0 or 1
• R 1 is cyano, acetyl or trifluoroacetyl
• R 2 is methyl or trifluoromethyl
• R 3 is (QC 1-4 alkoxy, trifluoromethoxy or a group of formula -O-SO 2 -R 14 , wherein
• R 14 is (C 1 -C 4 ) -alkyl, trifluoromethyl, (C 3 -C 6 ) -cycloalkyl, phenyl or thienyl,
• phenyl and thienyl may in each case be monosubstituted or disubstituted, identically or differently, with fluorine, chlorine, cyano, methyl, trifluoromethyl, methoxy and / or trifluoromethoxy,
• R is hydrogen, fluorine or methyl
• R 1 ' is ethyl, methoxy or trifluoromethoxy
• R 1 is cyano or acetyl
• R is methyl or trifluoromethyl
• R 3 is (QC 3 ) alkoxy or a group of the formula -O-SO 2 -R 14 , wherein
• R is (C 1 -C 3 ) -alkyl
• R 4 is hydrogen or methyl
• the invention further provides a process for the preparation of the compounds of the formula (I) according to the invention in which R 3 is (C 3 -C 7 ) -cycloalkyl-substituted (C 1 -C 6 ) -alkoxy, trifluoromethoxy or a group of the formula -O-SO 2 -R 14 , in which R 14 has the abovementioned meaning, characterized in that a compound of the formula (H)
• T is methyl or ethyl
• R 15 is (C 1 -C 6 ) -alkyl which may be substituted by (C 3 -C 7 ) -cycloalkyl or is trifluoromethyl,
• R 1 b ⁇ is methyl or ethyl
• X represents a leaving group, such as halogen, mesylate, tosylate or triflate
• Y represents a non-nucleophilic anion, such as tetrafluoroborate
• Suitable inert solvents for this purpose include, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, halogenated hydrocarbons such as dichloromethane, Tnchlormethan, carbon tetrachloride, T ⁇ chlorethan or 1, 2-dichloroethane, or other solvents such as Acetomt ⁇ l , Tetrahydrofuran, dioxane, 1,2-dimethoxyethane, hexane, benzene, toluene, chlorobenzene, pyridine or glacial acetic acid.
• alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol
• halogenated hydrocarbons such as dichloromethane, Tnchlormethan, carbon tetrachloride, T ⁇
• the reactions are preferably carried out in dichloromethane, toluene, ethanol or isopropanol at the respective reflux temperature under atmospheric pressure.
• the process steps (II) + (HI) + (IV) ⁇ (V) and (D) + (VE) + (VHI) ⁇ (VI) may optionally advantageously in the presence of an acid, an acid / base combination and / or a dehydrating agent, such as molecular sieve occur.
• Suitable acids are, for example, acetic acid, trifluoroacetic acid, methanesulfonic acid or p-toluenesulfonic acid; Pipe ⁇ din or Pyndm are particularly suitable as bases [cf.
• reaction with s-triazine in process step (V) - (VIa) is preferably carried out in N, N-dimethylformamide using ⁇ at ⁇ umhyd ⁇ d as the base [cf. J Klemschroth et al, Synthesis 1986, 859-860]
• Inert solvents for process (VI) + (K) ⁇ (IA), (VI) + (X) ⁇ (IA) and (VI) + (XS) ⁇ (IB) are, for example, ethers, such as diethyl ether, methyl tert butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, chloromethane, tetrachloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, t-chloroethylene, Chlorobenzene or chlorotoluene, or other solvents such as NN-dimethylformamide (DMF), dimethyl sulfox
• the process variant (VI) + (XI) -> (I-A) is preferably carried out with a large excess of orthoformate without the addition of another solvent;
• the reaction catalyst for example, strong inorganic acids such as sulfuric acid are advantageous [cf. e.g. LI. Barabanov et al, Russ Chem Bl 47 (11), 2256-2261 (1998)].
• Suitable bases for process step (VI) + (DC) ⁇ (IA) are, in particular, alkali metal or alkaline earth carbonates such as lithium, potassium, potassium, calcium or cesium carbonate, alkali metal hydroxides such as sodium or potassium hydoxide, amides such as lithium , ⁇ atnum or potassium bis (tmethylsilyl) amide or lithium d ⁇ sopropylamide, organometallic compounds such as butyl lithium or phenyllithium, or else phosphazene bases such as, for example, P2-t-Bu or P4-t-Bu [so-called "Schwesinger bases", cf. R. Schwesinger, H. Schlemper, Angew. Chem. Int. Ed. Engl. 26, 1167 (1987); T. Pietzonka, D. Seebach, Chem. Ber. 124, 1837 (1991)].
• sodium hydride or the phosphazene base P4-t-Bu is used.
• Suitable bases for process step (VI) + (XU) -> (IB) are in particular alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali metal hydrides such as sodium or potassium hydride, organometallic compounds such as butyl lithium or phenyllithium, or organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, N, N-diisopropylethylamine, pyridine, l, 5-diazabicyclo [4.3.0] non-5-ene (DB ⁇ ), 1,8-diazabicyclo- [5.4.0] undec-7-ene (DBU) or 1,4-diazabicyclo [2.2.2] octane (DABCO ®). Preference is given to using pyridine, which at the same time also serves as solvent.
• alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium
• the process step (VI) + (X) -> (I-A) is generally carried out without addition of a base.
• the reactions (VI) + (IX) ⁇ (IA), (VI) + (X) ⁇ (IA) and (VI) + (XII) ⁇ (IB) are generally carried out in a temperature range of -20 0 C to + 100 ° C, preferably at 0 0 C to +50 0 C; the process variant (VI) + (XI) ⁇ - (IA) is usually carried out in a temperature range of +100 0 C to +150 0 C.
• the reactions can be carried out at normal, elevated or reduced pressure (eg from 0.5 to 5 bar); generally one works at normal pressure.
• the compounds of the formula (II) are commercially available, known from the literature or can be prepared in analogy to processes known from the literature (see the following Reaction Schemes 1-7).
• the compounds of the formulas (HI), (W), (VII), (IX), (X), (XI) and (XU) are in many cases commercially available, known from the literature or can be prepared by methods known from the literature.
• VTS The compounds of the formula (VTS) are described in the literature or can be obtained analogously to processes known in the literature [cf. e.g. T. Searls, L.W. McLaughlin, Tetrahedron 55, 11985-11996 (1999); D. McNamara, P.D. Cook, J. Med. Chem. 30, 340-347 (1987); S. Nesnow, C. Heidelberger, J. Heterocycl. Chem. YI, 941-944 (1975); N.C. Hung, E. Bisagni, Synthesis 1984. 765-766].
• the compounds of the formula (I) according to the invention in which R 3 is (C 1 -C 6 ) -alkyl or mono- (C 1 -C 6 ) -alkylamino can be prepared analogously to methods known from the literature, for example starting from compounds of the formula (IB) in which R 14 is trifluoromethyl (see Reaction Scheme 10).
• the compounds according to the invention of the formula (I) in which R 3 is (C 1 -C 6) -alkylthio can be obtained in analogy to methods known from the literature, for example starting from compounds of the formula (VI) (see Reaction Scheme 11).
• the inventive compounds act as antagonists of the mineralocorticoid receptor and show an unpredictable, valuable pharmacological activity spectrum. They are therefore suitable for use as medicaments for the treatment and / or prophylaxis of diseases in humans and animals.
• the compounds according to the invention are suitable for the prophylaxis and / or treatment of various diseases and disease-related conditions, in particular diseases which are characterized either by an increase in the plasma aldosterone concentration or by a change in the aldosterone plasma concentration relative to the plasma renin concentration or go along with these changes.
• diseases which are characterized either by an increase in the plasma aldosterone concentration or by a change in the aldosterone plasma concentration relative to the plasma renin concentration or go along with these changes.
• diseases include: idiopathic primary hyperaldosteronism, hyperaldosteronism in adrenal hyperplasia, adrenal adenomas and / or adrenal carcinomas, hyperaldosteronism in cirrhosis, hyperaldosteronism in heart failure and (relative) hyperaldosteronism in essential hypertension.
• the compounds of the present invention are also useful for the prophylaxis of sudden cardiac death in patients at increased risk of dying from sudden cardiac death.
• patients e.g. Hypertension, heart failure, coronary artery disease, stable and unstable angina, myocardial ischemia, myocardial infarction, dilated cardiomyopathy, shock, arteriosclerosis, atrial and ventricular arrhythmia, transient and ischemic attacks, stroke, inflammatory cardiovascular disease, peripheral and cardiovascular diseases, peripheral circulatory disorders, pulmonary hypertension, spasm of the coronary arteries and peripheral arteries, thrombosis, thromboembolic disorders and vasculitis.
• the compounds according to the invention can furthermore be used for the prophylaxis and / or treatment of edema formation, for example pulmonary edema, renal edema or heart disease.
• edema formation for example pulmonary edema, renal edema or heart disease.
• Insufficiency-related edema, and restenosis such as after thrombolytic therapy, percutaneous transluminal angioplasty (PTA) and transluminal coronary angioplasty (PTCA), heart transplantation and bypass surgery
• the compounds of the invention are suitable for use as a diuretic and in electrolyte disorders such as hypercalcemia.
• the compounds of the invention can be used for the prophylaxis and / or treatment of diabetes mellitus and diabetic sequelae such as neuropathy and nephropathy, acute and chronic renal failure and chronic renal failure
• Another object of the present invention is the use of the compounds of the invention for the treatment and / or prevention of diseases, in particular the aforementioned diseases
• Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prevention of Erkran- kungen, in particular the aforementioned diseases.
• Another object of the present invention is a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention
• inventive compounds can be used alone or as needed in combination with other active ingredients.
• pharmaceutical compositions comprising at least one of the compounds according to the invention and one or more further active compounds, in particular for the treatment and / or prevention of the abovementioned disorders.
• Suitable combmating agents are exemplified and preferably mentioned:
• Active substances lowering the blood pressure by way of example and preferably from the group of the calcium antagonists, angiotensin Aü antagonists, ACE inhibitors, endothelin antagonists,
• Renm inhibitors alpha-receptor blockers, beta-receptor blockers and rho-kinase inhibitors
• Diuretics especially loop diuretics and thiazides and thiazide-like diuretics
• Antithrombotic agents by way of example and preferably from the group of thrombocyte aggregation inhibitors, anticoagulants or profilolytic substances;
• Lipid metabolism-altering agents by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR inhibitors alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors, and lipoprotein (a) antagonists;
• organic nitrates and NO donors such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-I, and inhaled NO;
• Positive inotropic compounds such as cardiac glycosides (digoxin), beta adrenergic and dopaminergic agonists such as isoproterenol, epinephrine, norepinephrine, dopamine and dobutamine;
• cGMP cyclic guanosine monophosphate
• cAMP cyclic adenosine monophosphate
• PDE phosphodiesterases
• sildenafil sildenafil
• Vardenafil tadalafil
• PDE 3 inhibitors such as amrinone and milrinone
• Natriuretic peptides e.g. atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP, Nesiritide), C-type natriuretic peptide (CNP) and urodilatin;
• ABP atrial natriuretic peptide
• BNP B-type natriuretic peptide
• CNP C-type natriuretic peptide
• urodilatin urodilatin
• Calcium sensitizers such as by way of example and preferably levosimendan
• NO-independent, but heme-dependent guanylate cyclase stimulators in particular the compounds described in WO 00/06568, WO 00/06569, WO 02/42301 and WO 03/095451;
• Guanylate cyclase NO- and heme-independent activators in particular the compounds described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510;
• HNE human neutrophil elastase
• the signal transduction cascade inhibiting compounds such as tyrosine kinase inhibitors, in particular sorafenib, imatinib, Gef ⁇ tinib and erlotinib; and or • the energy metabolism of the heart affecting compounds, such as by way of example and preferably etomoxir, dichloroacetate, ranolazines or trimetazidines.
• the compounds according to the invention are used in combination with a diuretic, such as by way of example and preferably furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichloromethiazide, chlorthalidone, indapamide, metolazone, quinethazone, Acetazolamide, dichlorophenamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.
• a diuretic such as by way of example and preferably furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichloromethia
• antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin AH antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, älpha receptor blockers, beta-receptor blockers, Rho-kinase inhibitors and diuretics.
• the compounds according to the invention are administered in combination with a calcium antagonist, such as by way of example and preferably nifedipine, amlodipine, verapamil or diltiazem.
• a calcium antagonist such as by way of example and preferably nifedipine, amlodipine, verapamil or diltiazem.
• the compounds according to the invention are administered in combination with an angiotensin Aü antagonist, such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embusartan.
• angiotensin Aü antagonist such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embusartan.
• the compounds according to the invention are administered in combination with an ACE inhibitor, such as by way of example and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
• an ACE inhibitor such as by way of example and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
• the compounds according to the invention are administered in combination with an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
• an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
• the compounds of the invention are administered in combination with a renin inhibitor, such as by way of example and preferably aliskiren, SPP-600 or SPP-800.
• a renin inhibitor such as by way of example and preferably aliskiren, SPP-600 or SPP-800.
• the compounds according to the invention are administered in combination with an alpha-1-receptor blocker, such as by way of example and preferably prazosin.
• the compounds according to the invention are used in combination with a beta-receptor blocker such as, by way of example and by way of preference, propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipropanol, nadolol, mepindolol, carazalol, Sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, Carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol,
• a beta-receptor blocker such as, by
• the compounds according to the invention are used in combination with a rho-kinase inhibitor, such as, for example and preferably, Fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI- 23095 or BA-1049.
• a rho-kinase inhibitor such as, for example and preferably, Fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI- 23095 or BA-1049.
• Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances.
• the compounds according to the invention are administered in combination with a platelet aggregation inhibitor such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.
• a platelet aggregation inhibitor such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.
• the compounds according to the invention are administered in combination with a thrombin inhibitor, such as, by way of example and by way of preference, ximelagatran, melagatran, bivalirudin or Clexane.
• a thrombin inhibitor such as, by way of example and by way of preference, ximelagatran, melagatran, bivalirudin or Clexane.
• the compounds according to the invention are administered in combination with a GP ⁇ b / HIa antagonist, such as, by way of example and by way of preference, tirofiban or abciximab.
• a GP ⁇ b / HIa antagonist such as, by way of example and by way of preference, tirofiban or abciximab.
• the compounds according to the invention are used in combination with a factor Xa inhibitor, such as by way of example and preferably rivaroxaban (BAY 59-7939), DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD No. 3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
• a factor Xa inhibitor such as by way of example and preferably rivaroxaban (BAY 59-7939), DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD No. 3112, YM-150, KFA-1982, EMD-503982, MCM
• the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
• LMW low molecular weight
• the compounds according to the invention are administered in combination with a vitamin K antagonist, such as, by way of example and by way of preference, coumarin.
• lipid metabolizing agents are preferably compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors, PPAR alpha- , PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein (a) antagonists understood.
• CETP inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
• ACAT inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
• MTP inhibitors MTP inhibitors
• PPAR alpha- , PPAR gamma and / or PPAR delta agonists cholesterol absorption inhibitors
• polymeric bile acid adsorbers bile acid rea
• the compounds according to the invention are used in combination with a CETP inhibitor such as, for example and preferably, torcetrapib (CP-529 414), JJT-705, BAY 60-5521, BAY 78-7499 or CETP vaccine (Avant). administered.
• a CETP inhibitor such as, for example and preferably, torcetrapib (CP-529 414), JJT-705, BAY 60-5521, BAY 78-7499 or CETP vaccine (Avant). administered.
• the compounds of the invention are administered in combination with a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
• a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
• the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins such as, for example and preferably, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin.
• statins such as, for example and preferably, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin.
• the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494 or TAK-475.
• a squalene synthesis inhibitor such as by way of example and preferably BMS-188494 or TAK-475.
• the compounds according to the invention are administered in combination with an ACAT inhibitor, such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
• an ACAT inhibitor such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
• the compounds according to the invention are administered in combination with an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
• an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
• the compounds according to the invention are administered in combination with a PPAR-gamma agonist, such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
• a PPAR-delta agomsten by way of example and preferably GW-501516 or BAY 68-5042.
• the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
• a cholesterol absorption inhibitor such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
• the compounds according to the invention are administered in combination with a lipase inhibitor, such as by way of example and preferably Orhstat.
• the compounds according to the invention are administered in combination with a polymeric bile acid adsorbent, such as by way of example and preferably cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
• a polymeric bile acid adsorbent such as by way of example and preferably cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
• ASBT IBAT
• the compounds according to the invention are administered in combination with a lipoprotein (a) antagonist, such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.
• a lipoprotein (a) antagonist such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.
• Another object of the present invention smd drugs containing at least one inventive compound, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above
• the compounds according to the invention can act systemically and / or locally.
• they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctivae otic or as an implant or stent
• the compounds according to the invention can be administered in suitable administration forms.
• the compounds of the invention rapidly and / or modified donating application forms that the Compounds according to the invention in crystalline and / or amorphised and / or dissolved form, such as tablets (uncoated or coated tablets, for example, with enteric or delayed-dissolving or insoluble coatings, which control the release of the compound of the invention) in the oral cavity quickly disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules), dragées, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
• Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarte ⁇ ally, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscular, subcutaneous, mtracutan, percutaneous or intraperitoneal).
• a resorption step e.g., intravenously, intraarte ⁇ ally, intracardially, intraspinal, or intralumbar
• absorption e.g., intramuscular, subcutaneous, mtracutan, percutaneous or intraperitoneal.
• parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
• Inhalation medicaments including powder inhalers, nebulizers
• nasal drops solutions or sprays
• lingual, sublingual or buccal tablets films / wafers or capsules
• suppositories ear or ophthalmic preparations
• vaginal capsules aqueous suspensions (lotions, shake mixtures)
• lipophilic suspensions ointments
• creams transdermal therapeutic systems (eg plasters)
• milk pastes, foams, powdered powders, implants or stents.
• the compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable Hüfstoffe.
• These adjuvants include, among others. Excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitol oleate), binders (for example polyvinylpyrrohdone), synthetic and natural polymers (for example albumin), Stabilizers (eg, antioxidants such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides) and flavor and / or odoriferous.
• Excipients for example microcrystalline cellulose, lactose, mannitol
• solvents for example liquid polyethylene glycols
• the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg of body weight.
• Device type MS Micromass ZQ
• Device type HPLC Waters Alliance 2795; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 liter of water + 0.5 ml of 50% ant acid, eluent B. 1 1 acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 mm 90% A ⁇ 2.5 now 30% A ⁇ 3 ⁇ min 5% A ⁇ 4 5 min 5% A, flow: 0 0 min 1 ml / min -> 2.5 ⁇ un / 3.0 min / 4.5 min 2 ml / now; Oven 50 ° C; UV detection: 210 nm.
• Device type MS Micromass ZQ, device type HPLC: HP 1100 seconds; UV DAD; Column Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20mm x 4mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0 0 mm 90% A ⁇ 2.5 min 30% A ⁇ 3 0 min 5% A ⁇ 4 5 mm 5% A; Flow: 0.0 mm 1 ml / now ⁇ 2.5 mm / 3.0 mm / 4.5 mm 2 ml / min; Oven 50 ° C, UV detection - 210 nm
• Device type MS Micromass ZQ; Device type HPLC- HP 1100 Se ⁇ es; UV DAD, column Phenomenex Gemmi 3 ⁇ 30 mm ⁇ 3 00 mm, eluent A: 1 1 water + 0 5 ml 50% formic acid, eluent B. 1 l acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 mm 90% A ⁇ 2.5 min 30% A ⁇ 3 0 mm 5% A ⁇ 4 5 min 5% A, flow: 0 0 min 1 ml / mm ⁇ - 2 5 min / 3.0 min / 4.5 mm 2 ml / mm, oven 50 0 C, UV detection 210 nm
• Device Type MS Waters ZQ
• Device type HPLC Waters Alliance 2795
• Column Phenomenex Onyx Monolithic C18, 100 mm x 3 mm
• Eluent A 1 l of water + 0.5 ml of 50% formic acid
• eluent B 1 l of acetonitrile + 0.5 ml of 50% formic acid
• Gradient 0.0 min 90% A ⁇ 2 min 65% A ⁇ 4.5 min 5% A ⁇ 6 min 5% A
• Flow 2 ml / min
• Oven 4O 0 C
• UV detection 210 nm.
• 9-oxo-9H-fluorene-4-carboxylic acid methyl ester (9 85 g, 41 3 mmol) is initially charged in 180 ml of anhydrous THF At RT within 90 min RED-AL ® (38 ml, 136 mmol) [Natminum] bis (2-methoxyethoxy) aluminum Dihyd ⁇ d, 70% solution in toluene] was added dropwise and the reaction mixture stirred for 1 h The mixture is hydrolyzed by careful dropwise addition of 15 ml of water Then, 60 ml of 6 N hydrochloric acid and extracted with ethyl acetate (4 x 150 ml each).
• Example I IA The compound from Example I IA (5.21 g, 25.0 mmol) is initially charged in 180 ml of dichloromethane, and the compound from Example 2OA (2 89 g, 27.5 mmol), acetic acid (1.72 ml, 30.0 mmol) and
• the suspension is extracted three times with 20 ml of ethyl acetate and the combined organic phases are washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic solution is dried over magnesium sulfate and concentrated. The residue (0.6 g) is used without further purification in the next step.
• the resulting crude product which consists to about 50% of 3-trifluoromethyl-4- [2- (dimethylammo) vinyl] - benzomt ⁇ l, is taken up in 500 ml of THFA water (1: 1) and mixed with 8.20 g (38.3 mmol) ⁇ atriumpenodat. It is stirred for 18 h at room temperature and then the precipitate separated by filtration. The filtrate is mixed with saturated Nat ⁇ umhydrogen- carbonate solution and extracted three times with ethyl acetate. The combined organic phases are dried with sodium sulfate and the solvent is removed on a rotary evaporator.
• the crude product is dissolved in 800 ml of dichloromethane / methanol in the heat, treated with 500 ml of ethyl acetate and then concentrated again to a volume of 50 ml.
• the precipitated product is filtered off and washed with ethyl acetate and diethyl ether. After drying in a high vacuum, 3.63 g (99% of theory) of the title compound are obtained in the form of yellowish crystals.
• the Beauverbmdung is analogous to Example 10 from 50 mg (0.13 mmol) of 3-acetyl-2-methyl-4- (2-methyl-4-oxo-4H-chromen-8-yl) -4,6-dihydro-l, 6-naphthyridin-5 (1H) -one and 22 mg (0.15 mmol) cyclopropanesulfonic acid chloride are obtained. 54 mg (84% of theory) of the product are obtained as a pale yellow solid.
• I g of the racemate from Example 25 are separated into the enantiomers by means of HPLC on a chiral phase (column: 630 mm ⁇ 30 mm; silica gel phase based on the chiral selector poly (N-methacryloyl-D-leucine tert-butylamide; Eluent: isohexane / ethyl acetate 1: 1, temperature: 24 ° C, flow: 25 ml / mm, UV detection: 260 nm).
• Residue is purified by preparative HPLC (eluent acetonitrile / water with 0 1% formic acid, gradient 20 80 ⁇ 95 5). 23 mg (42-8% of theory) of the title compound are obtained
• the crude product is purified by column chromatography (silica gel, mobile phase: cyclohexane / acetic acid ethyl ester 1: 1)
• the product thus obtained is crystallized from ethyl acetate. 451 mg (22% of theory) of the title are obtained as a white solid.
• the racemate from Example 35 can be used on a preparative scale by chiral phase HPLC in its enantiomers [column 680 mm x 40 mm; Silica gel phase based on the chiral selector poly (N-methacryloyl-D-leuca- dicyclopropylmethylamide; eluent ethyl acetate / isohexane 2.1 (v / v), temperature 24 ° C., flow 80 ml / min, UV detection: 220 nm].
• the precipitate is washed with ethyl acetate and diethyl ether and then purified by flash chromatography.
• the product fractions are combined, concentrated on a rotary evaporator and the residue is then crystallized from ethyl acetate. After drying in a high vacuum, 1160 mg (30% of theory) of the title compound are obtained in the form of yellowish crystals.
• the racemate from Example 37 can be separated into its enantiomers by HPLC on a chiral phase on a preparative scale [column 670 mm ⁇ 40 mm; Silica gel phase based on the chiral selector poly (N-methacryloyl-L-leucine-tert-butylamide, eluent: ethyl acetate / isohexane 7 3 (v / v), temperature 24 ° C. , flow 80 ml / min, UV detection : 220 nm].
• MR mineralocorticoid receptor
• CHO Kl cell line an established chimera system is used in which the ligand-binding domains of human steroid hormone receptors are fused to the DNA binding domain of the yeast transcription factor GAL4.
• the resulting GAL4 steroid hormone receptor chimeras are co-transfected in the CHO cells with a reporter construct and stably expressed.
• the GAL4 DNA binding domain (amino acids 1-147) from the vector pFC2-dbd (from Stratagene) with the PCR-amplified ligand-binding domains of the mineralocorticoid receptor (MR , Amino acids 734-
• glucocorticoid receptor amino acids 443-777
• progesterone receptor PR
• the reporter construct which contains five copies of the GAL4 binding site, upstream of a thymidine kinase promoter, leads to the expression of the firefly
• Luciferase (Photinus pyralis) after activation and binding of the GAL4 steroid hormone receptor Chimeras by the specific agonists Aldosterone (MR), Dexamethasone (GR), Progesterone (PR) and Dihydiotestosterone (AR)
• MR, GR, PR and AR cells are seeded in medium (Optimem, 2.5% FCS, 2mM glutamine, 10mM HEPES) in 96- (or 384- or 1536-) well microtiter plates the day before testing plated and held in a cell incubator (96% humidity, 5% v / v CO 2 , 37 ° C). On test day, the substances to be tested are taken up in the above-mentioned medium and added to the cells.
• the luciferase activity is measured with the aid of a video camera
• the measured relative light units give a sigmoidal stimulation curve as a function of the substance concentration
• the IC 50 values are calculated with the help of the Computer program GiaphPad PRISM (Version 3 02)
• Table A shows the IC 50 wide (MR) repiasentative examples.
• Cerebral cortex membrane preparations from Wistar rats serve as the starting material for a radioactive binding assay, which is described in detail as a standard assay in the literature [Ehlert, FJ, Roeske, WR, Itoga E, Yamamura, HI, Life Sa. 30, 2191-2202 ( 1982), Gould, RJ, Murphy, KMM, Snyder, SH, Proc. Natl. Acad.
• test compounds in DMSO typically labeled tritium for 90 minutes at 25 0 C in a 50 mM T ⁇ sHCl buffer, pH 7.7, with the membrane preparations and the ligand nitrendipine (0.1 nM) and the specific binding dei Testveibmdonne about quantification specifically displaced the, radioactive labeled ligand determines IC 50 values are determined via a non-linear regression analysis
• an IC 50 value of 0.3 nM is determined for a classical dihydropyridm-type calcium antagonist, such as nitrendipine, while investigated examples of the compounds of the invention described herein have IC 50 values> 1 ⁇ M, and thus an affinity to the L-type calcium channel which is at least a factor of 3000, have low levels of binding to the L-type calcium channel.
• a classical dihydropyridm-type calcium antagonist such as nitrendipine
• the concentration of the test substances increases by a factor of 10 for each of the following four contractions Base tension and the many forward contraction value set as 100%, the following contraction peaks refer to this value.
• This experimental procedure allows the differentiation of calcium-agonistic (slight increase in submaximal contraction, greater increase with minimal contraction) and calcium-antagonistic substance action (reduction in submaximal contraction, greater reduction with minimal contraction).
• an ICs 0 value of 0.1 nM to 0.4 nM is measured for a classic calcium antagonist of the dihydropy ⁇ din type, such as nifedipine, while investigated examples of the compounds according to the invention described here have IC 50 values of> 1 ⁇ M and thus have an affinity for the L-type calcium channel that is at least reduced by the factor 2500.
• Compounds with such a low residual affinity for the L-type calcium channel no longer show pronounced hemodynamic effects in vivo beyond the L -Type calcium channel are mediated
• Wistar rats 250-350 g body weight are kept with free access to food (Altromin) and drinking water. From 72 hours before the start of the experiment, instead of the normal fur, the animals receive only salt-reduced food containing 0.02% sodium chlo ⁇ d ( ssmff RTM-H, 10 mm with 0.02% Na, S0602-E081, Fa. ssniff Spezialdi decisiven GmbH, D-59494 Soest). During the experiment, the tails are kept individually for about 24 hours in metabolic cages suitable for rats of this weight class (Tecmplast Germany GmbH, D-82383 Hohenpeissenberg) with free access to salt-reduced food and drinking water.
• the substance to be tested is administered to the animals in a volume of 0.5 ml / kg body weight of a suitable solvent in the stomach by means of a gavage.
• a control serving Tieie receive only solvents.
• Controls and substance tests are carried out in parallel on the same day.
• Control groups and substance dose groups each consist of 3 to 6 animals During the experiment, the urine excreted by the animals is continuously collected in a collecting container on the bottom of the cage. The intrinsic volume per unit time is determined separately for each animal, and the concentration of the sodium or potassium ions excreted in the urine is measured by means of standard flame photometric methods.
• the Nat ⁇ um / Kahum quotient is calculated as a measure of the substance effect
• the measurement intervals are typically the period up to 8 hours after the start of the test (daytime divi) and the period of 8 to 24 hours after the start of the experiment (night interval).
• the urine is collected and measured every two hours during the day interval.
• the animals at the beginning of the test and then at intervals of two hours by gavage a defined amount of water supplied.
• DHA desoxycorticosteioacetate
• high salt diet high salt diet
• unilateral renal degeneration induces hypertension in the rat which is characterized by relatively low levels of renin.
• DOCA desoxycorticosteioacetate
• test substances can thus be examined for existing antihypertrophic and end organ protective effect
• Unmetrophrected SD rats eL keep 1% sodium chloride in the drinking water and once weekly a subcutaneous injection of desoxycorticosterone acetate (dissolved in sesame oil, Sigma) between the scapegrae injected (high dose 100 mg / kg / week sc, normal dose: 30 mg / kg / Week sc).
• the substances which are to be tested for their positive effect in vivo are administered by gavage or by the feed (Fa. Ssmff).
• the substances are administered once a day for 4-8 weeks by gavage or by food.
• the placebo group used are tiebies, which are treated in the same way, but receive either only the solvent or the feed without test substance
• Heart rate inotropy (dp / dt), relaxation time (tau), maximum left ventricular pressure, left ventricular end-diastolic pressure (LVEDP)], weight determination of heart, kidney and
• Lung measurement of protein excretion and by measuring gene expression of markers (eg ANP, Atrial Natriuretic Peptide, and BNP, Brain Natriuretic Peptide) by RT / TaqMan PCR after RNA isolation from cardiac tissue.
• markers eg ANP, Atrial Natriuretic Peptide, and BNP, Brain Natriuretic Peptide
• the statistical evaluation is done with Student's t-test after checking the variances for homogeneity.
• the compounds according to the invention can be converted into pharmaceutical preparations as follows
• the mixture of compound, lactose and starch according to the invention is mixed with a 5% solution (m / m) of the PVP in water.
• the granules are mixed with the magnesium stearate for 5 minutes after drying.
• This mixture is compressed with a conventional tablet press (format of Tablet see above) As a guideline for the compression, a pressing force of 15 kN is used
• a single dose of 100 mg of the compound according to the invention corresponds to 10 ml of oral suspension.
• the rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension.
• the egg is added at rest.
• the whisker is allowed to boil until the swelling of the rhodiol has ended
• a single dose of 100 mg of the compound according to the invention corresponds to 20 g of oral solution.
• the inventive composition was suspended in the mixture of polyethylene glycol and polysorbate with stirring.
• the Ruhr process is set up until complete dissolution of the compound according to the invention.
• composition of the invention was dissolved at a concentration below saturation solubility in a physiologically inert solvent (e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%).
• a physiologically inert solvent e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%.
• the solution is filtered ste ⁇ l and filled ste ⁇ le and pyrogen-free Injetechnischsbehaltmsse

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